Article Type: Clinical Article

Accepted Article
Changes in ultrasonography indicators of abnormally invasive placenta during

pregnancy

Giuseppe Calì 1, Ilan E. Timor-Trisch 2, Josè Palacios-Jaraquemada 3, Ana

Monteaugudo 2, Francesco Forlani 1,Gabriella Minneci 1, Francesca Foti 1, Danilo

Buca 4, Alessandra Familiari 5, Giovanni Scambia 5, Marco Liberati 4, Francesco

D’Antonio 6,7*

1
Department of Obstetrics and Gynaecology, Arnas Civico Hospital, Palermo, Italy.
2
Department of Obstetrics and Gynaecology, Division of Maternal–Fetal Medicine,

New York University SOM, New York, NY, USA.

3
Centre for Medical Education and Clinical Research (CEMIC), University Hospital,

Buenos Aires, Argentina.

4
Department of Obstetrics and Gynaecology, University of Chieti, Chieti, Italy.
5
Department of Maternal-Fetal medicine, Catholic University of the Sacred Heart,

Rome, Italy.
6
Women´s Health and Perinatology Research Group, Department of Clinical

Medicine, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø,

Norway.
7
Department of Obstetrics and Gynecology, University Hospital of Northern Norway,

Tromsø, Norway.

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1002/ijgo.12413
This article is protected by copyright. All rights reserved.
 *
Corresponding author: Francesco D’Antonio

Department of Obstetrics and Gynaecology, University Hospital of Northern Norway,

Accepted Article
Department of Clinical Medicine, Faculty of Health Sciences, UiT - The Arctic

University of Norway, Hansine Hansens veg 18, 9019 Tromsø, Norway.

E-mail address: francesco.dantonio@uit.no

ABSTRACT

Objective: To ascertain whether the prevalence of ultrasonography signs of

abnormally invasive placenta (AIP) change during pregnancy.

Methods: The present retrospective analysis included women with a prenatal

diagnosis of AIP that was confirmed at delivery between January 1, 2007, and April

30, 2017, at the Department of Obstetrics and Gynaecology, Arnas Civico Hospital,

Palermo, Italy. Ultrasonography signs of AIP were recorded at four different intervals

during pregnancy: early first (6–9 weeks), first (11–14 weeks), second (15–24

weeks), and third trimester (25–36 weeks).

Results: There were 105 pregnancies included. Low implantation of the gestational

sac was present on all ultrasonography images from the early first trimester

compared with on 23 of 83 (27.7%) images from 11–14 weeks of pregnancy. The

identification of loss of the clear space, placental lacunae, bladder wall interruption,

and uterovesical hypervascularity all increased (all P<0.001) from the early first

trimester onwards; these could all be identified in a majority of patients at 11–14

weeks of pregnancy

This article is protected by copyright. All rights reserved.

 Conclusions: The prevalence of ultrasonography signs suggestive of AIP varied

throughout pregnancy. During the early first trimester, indicators of AIP were similar
Accepted Article
to those of a cesarean scar pregnancy; classical ultrasonography signs of AIP were

already present at 11–14 weeks of pregnancy for most patients.

Keywords: Abnormal invasive placenta; Placenta accreta; Signs of placental

invasion; Ultrasound.

Synopsis: The prevalence of ultrasonography signs suggestive of abnormally

invasive placenta changed through pregnancy; the prevalence was higher in

placenta percreta compared with accreta or increta.

1. Introduction

The increasing incidence of abnormally invasive placenta (AIP) over the last two

decades poses a significant challenge for maternal–fetal medicine practitioners [1].

Accurate prenatal diagnosis of AIP is fundamental because it has been shown to

reduce the burden of maternal and fetal morbidity associated with this condition,

such as severe hemorrhage, need for blood transfusion, peripartum hysterectomy,

and intra- and post-operative adverse events, particularly by allowing the

implementation of pre-planned management strategies [1–5].

Prenatal diagnosis of AIP is commonly accomplished using ultrasonography, with

magnetic resonance imaging (MRI) performed for those patients with inconclusive

ultrasonography findings to better delineate the extension and the topography of

placental invasion [6–9].

This article is protected by copyright. All rights reserved.

 Ultrasonography assessment of women at high risk of AIP is usually performed

during the second and third trimester of pregnancy, and has been shown to have
Accepted Article
good overall diagnostic accuracy, especially when a combination of maternal

characteristics and imaging signs are integrated into an individualized diagnostic

algorithm [10]. However, recent reports have suggested that ultrasonography signs

of AIP can be detected as early as in the first trimester of pregnancy [11, 12].

Further, the recently proposed association between cesarean scar pregnancy and

AIP [5, 6] poses the question of whether all women with a previous cesarean delivery

should be screened for cesarean scar pregnancy and whether ultrasonography

assessments to rule out AIP should be started during the first trimester of pregnancy.

Finally, it is unknown whether the prevalence of classical ultrasonography signs of

AIP change throughout pregnancy; consequently, the optimal point during pregnancy

for examining patients at risk for AIP has yet to be elucidated. This is of fundamental

importance because it is plausible that early detection of AIP could improve patient

outcomes [12–13].

The primary aim of the present study was to ascertain whether the prevalence of

ultrasonography signs of AIP change through pregnancy; a secondary aim was to

explore whether the distribution of such signs was related to the severity of placental

invasion.

2. Materials and methods

The present retrospective observational analysis included all patients with a prenatal

diagnosis of AIP that was confirmed following a delivery referred to the Department

of Obstetrics and Gynaecology, Arnas Civico Hospital, Palermo, Italy, a regional

This article is protected by copyright. All rights reserved.

 referral center for AIP, between January 1, 2007, and April 30, 2017. Patients were

identified from an electronic database of the fetal medicine unit and delivery details
Accepted Article
were retrieved from hospital maternity records. Operative notes were checked and

details of operative findings and interventions performed were retrieved. Only

patients who had ultrasonography images that allowed the relationship between the

placenta, myometrium, and the bladder to be assessed were included in the present

study. Patients with ultrasonography images that did not allow such assessments

were excluded. The institutional review board of Arnas Civico Hospital approved the

study; given the retrospective nature of the study, specific informed consent was not

sought from the patients included.

All patients were evaluated prospectively using two-dimensional gray-scale and color

Doppler ultrasonography during the second and third trimesters of pregnancy (15–36

weeks of pregnancy) owing to the presence of placenta previa and prior cesarean

delivery. Further, ultrasonography images from the early first (6–9 weeks) and first

(11–14 weeks) trimester of pregnancy were retrieved from the fetal medicine unit

electronic database, when available; no examinations were performed at 10 weeks

of pregnancy. Since 2013, in view of the proposed association between cesarean

scar pregnancy and AIP, study institution policy has indicated that a systematic

prospective assessment of women at risk of AIP, such as those with a previous

cesarean delivery, be performed starting in the early first trimester of pregnancy to

assess the relationship between the gestational sac and the cesarean scar, and to

look for classical ultrasonography signs of AIP.

This article is protected by copyright. All rights reserved.

 All ultrasonography images were assessed for the presence of each sign suggestive

of AIP by two different researchers (G.C. and F.D.A.) with extensive expertise in
Accepted Article
assessing AIP disorders; both researchers were masked to final pathology reports

for the patients. Further, for those ultrasonography assessments performed during

the second and third trimesters of pregnancy, the presence and prevalence of each

ultrasonography sign explored were examined.

The ultrasonography signs suggestive of AIP [14] included were: (1) loss of clear

zone, defined as a loss or irregularity of the hypoechoic plane in the myometrium

underneath placental bed (the “clear zone”); (2) placental lacunae, defined as the

presence of numerous lacunae, often containing turbulent flow, visible on grayscale

or color Doppler ultrasonography; (3) bladder wall interruption, defined as loss or

interruption of bright bladder wall (hyperechoic band or “line” between uterine serosa

and bladder lumen); (4) uterovesical hypervascularity, defined as a striking color

Doppler signal observed between the myometrium and the posterior wall of the

bladder, including vessels appearing to extend from the placenta, across the

myometrium and beyond the serosa into the bladder or other organs, frequently

running perpendicular to the myometrium; (5) vascular invasion of the parametria,

defined as the presence of hypervascularity extending beyond the lateral uterine

walls and involving the region of the parametria.

All these signs were assessed at four different pregnancy intervals: the early first (6–

9 weeks), first (11–14 weeks), second (15–24 weeks) and third (25–36 weeks)

trimester. Further, in patients examined in the early first and first trimesters, the

position of the gestational sac compared to the cesarean scar was assessed and the

This article is protected by copyright. All rights reserved.

 incidence of a low or middle implantation of the gestational sac was recorded. Low

implantation of the gestational sac was diagnosed when the lower placental edge or
Accepted Article
the gestational sac were within or in close proximity to the area of the cesarean scar;

middle implantation was defined as the upper placental edge or gestational sac

implanted away from its normal position in the fundal part of the uterus but not

embedded or in close proximity to the previous cesarean scar. Ultrasonography

assessment was performed via transvaginal ultrasonography in the early first

trimester of pregnancy and by transabdominal ultrasonography at all the other time

points, as described previously [15]. All examinations were performed using 4.0–6.0

MHz curved transabdominal or 5.0–7.0 MHz endovaginal transducers; when

performing color Doppler ultrasonography, the pulsed rate frequency was set lower

at 1.3 kHz to identify the presence of placental lacunar flow.

Final diagnoses AIP types were made after surgery and hysterectomy based on the

pathological examination of the removed uterus. Placenta accreta was diagnosed

when anchoring placental villi were attached to the myometrium, placenta increta

was diagnosed when chorionic villi penetrated into the myometrium, and placenta

percreta was diagnosed when chorionic villi penetrated through the myometrium to

the uterine serosa (or adjacent organs) [16].

The prevalence of each ultrasonography sign was compared among the different

pregnancy trimesters using the χ2 test for trend. Where a direct comparison was

made between two values, intervals were compared using the Fisher exact test.

Finally, a sub-analysis was performed with data stratified by the depth of placental

This article is protected by copyright. All rights reserved.

 invasion; comparisons were made between patients with placenta accreta or increta,

and those with placenta percreta at histopathological analysis.

Accepted Article
Statistical analyses were performed using StatsDirect (StatsDirect, Altrincham, UK)

and SPSS version 15.0 (SPSS, Chicago, IL, USA). All tests were two tailed and

P<0.05 was considered statistically significant. STROBE guidelines for observational

studies were followed [17].

3. Results

There were 105 pregnancies with AIP confirmed at histopathological examination

following a cesarean hysterectomy that were identified and included in the study

(Table 1). All patients had placenta previa and at least one previous cesarean

delivery. There were 57 (54.3%, 95% confidence interval [CI] 44.3–64.4) patients

with placenta accreta/increta and 48 (45.7%, 95% CI 36.0–55.7) with placenta

percreta. The proportion of patients with ultrasonography images available for

analysis from the early first, first, second, and third trimesters were 64.8% (95% CI

54.8–73.8; n=68), 79.0% (95% CI 70.0–86.4; n=83), 100% (95% CI 96.5–100.0;

n=105), and 100% (95% CI 96.5–100.0; n=105), respectively. There was full

agreement between the two researchers regarding the type of ultrasonography signs

visible in all images; further, for ultrasonography images from the second and third

trimester of pregnancy, there was also complete agreement between the two

researchers and the original examiner.

When considering ultrasonography signs of AIP that were identifiable in the early first

trimester of pregnancy, low implantation of the gestational sac was observed for all

patients included whereas this sign could be identified in only 27.7% of images taken

This article is protected by copyright. All rights reserved.

 during the first trimester (P<0.001) (Table 2). The remaining signs of AIP included

were not present in any images obtained during the early first trimester whereas a
Accepted Article
loss of the clear space, placental lacunae, bladder wall interruption, and uterovesical

hypervascularity were identified in 84.3% (95% CI 74.7–91.4; n=70), 78.3% (95% CI

67.9–86.6; n=65), 75.9% (95% CI 65.3–84.6; n=63), and 51.8% (95% CI 40.6–62.9;

n=43) of the 83 images from the first trimester, respectively (all P<0.001) (Table S1).

Finally, signs of vascular invasion of the parametria were detected in none of the

images from the early first trimester compared with 18.1% (95% CI 10.5–28.0; n=15)

of images from the first trimester (P<0.001) (Table S2).

The proportion of ultrasonography images where a loss of clear space, placental

lacunae, bladder wall interruption, and uterovesical hypervascularity could be

visualized increased significantly from the early first trimester onwards (all P<0.001);

this trend was also observed when the data were stratified by placenta

accreta/increta or placenta percreta (all P<0.001) (Table 2). However, despite this

overall trend, the large majority of ultrasonography signs suggestive of AIP were

already visible on images from the first trimester. Loss of the clear space was

present in 84.3% of images from the first trimester, compared with 88.6% of those

from the second trimester (P=0.517), and bladder wall interruption was visible in

75.9% and 87.6% of images from the first and second trimesters, respectively

(P=0.052) (Table 2). Conversely, the increases in the visualization of placental

lacunae, uterovesical hypervascularity, and vascular invasion of the parametria

observed between the first and second trimester of pregnancy (Table 2) were

significant (all P<0.001) (Table S2). When comparing the second and third trimester

This article is protected by copyright. All rights reserved.

 of pregnancy, there was no difference in the visualization of any of the ultrasound

signs of AIP explored in the present study, irrespective of the depth of placental
Accepted Article
invasion (Table S3).

The proportion of patients with ultrasonography signs of AIP was compared based

on the extent of placental invasion (placenta accreta/increta compared with placenta

percreta) (Table 3). There was no difference in the proportion of images from cases

of placenta accreta/increta and placenta percreta showing a low implantation of the

gestational sac at either the early first trimester or first trimester. Among images

taken during the first trimester, the proportion with bladder wall interruption

identifiable was higher among images from patients with placenta percreta compared

with accreta/increta (P=0.010) (Table 3). In the second and third trimester of

pregnancy the proportion of images where loss of the clear zone, bladder wall

interruption, uterovesical hypervascularity, and vascular invasion of the parametria

could be identified was significantly higher among patients with a histopathological

diagnosis of placenta percreta compared with placenta increta/accreta; there was no

difference for the proportion of images showing placental lacunae (Table 3).

Examples of the different ultrasonography signs of AIP at different points in

pregnancy are presented in Figure 1.

4. Discussion

The findings of the present study demonstrated that the prevalence of

ultrasonography signs suggestive for AIP changed during pregnancy. In the early

first trimester of pregnancy (6–9 weeks), the prominent ultrasonography signs of AIP

were those of cesarean scar pregnancy and low implantation of the gestational sac

This article is protected by copyright. All rights reserved.

 within or near the cesarean scar; these were present in all the images included,

irrespective of the severity of placental invasion. A low implantation of the gestational

Accepted Article
sac was not identifiable at 11–14 weeks of pregnancy in the large majority of images;

however, most of the classical ultrasonography signs of AIP, such as loss of the

clear space, placental lacunae, bladder wall interruption, and uterovesical

hypervascularity, were already present at the time of the nuchal scan, although their

prevalence did increase with advancing pregnancy. Finally, the prevalence of

bladder wall interruption was higher among images from patients with placenta

percreta compared with placenta accreta/increta during the first trimester of

pregnancy; in the second and third trimesters of pregnancy, all ultrasonography

signs of AIP except placental lacunae were more prevalent among patients with

placenta percreta.

The recently suggested association between cesarean scar pregnancy and AIP [5, 6]

poses the dilemma of whether women at risk should begin AIP screening from early

pregnancy. The data from the present study demonstrated that low implantation of

the gestational sac in the early first trimester (6–9 weeks) was present for all patients

with AIP, irrespective of the severity of placental invasion whereas the other classical

signs of AIP, such as placental lacunae, loss of the clear zone, bladder wall

interruption, and uterovesical hypervascularity, were only detected from 11 weeks of

pregnancy. This poses the question of whether the assessment of the relationship

between the sac and the cesarean scar should be implemented in clinical practice to

stratify AIP risk in patients who are considered at risk. AIP is still a relatively rare

anomaly and screening all patients with at least one previous cesarean delivery to

look for a condition with a low prevalence could appear unfeasible, leading to

This article is protected by copyright. All rights reserved.

 unnecessary parental anxiety; conversely, it is plausible that early detection of AIP

could improve maternal outcomes.

Accepted Article
Despite this, prenatal management protocols when cesarean scar pregnancy is

diagnosed in asymptomatic patients are still a long way from being established. It

has been suggested previously that cesarean scar pregnancy is affected by a high

burden of adverse outcomes, such as severe hemorrhage, uterine rupture and need

for hysterectomy [8]. However, this evidence comes from small series including

mainly symptomatic patients. Although at least a proportion of women with a first

trimester diagnosis of cesarean scar pregnancy can progress to viability and

successful pregnancy outcomes, it has still to be elucidated how to differentiate

women with cesarean scar pregnancy who will develop AIP and those who will

experience short-term adverse events, such as severe hemorrhage or uterine

rupture [11-13]. Assessing the relationship between the ectopic gestational sac,

cesarean scar, and the anterior uterine wall has been suggested to be useful in

counseling women with a prenatal diagnosis of cesarean scar pregnancy [18]. Kaelin

Agten et al. [18] showed that cesarean scar pregnancy implanted “on the scar”,

defined as a placenta implanted partially or fully on top of a well healed scar,

demonstrated substantially better outcomes compared with patients with the

cesarean scar pregnancy implanted into the niche of a deficient or dehiscent scar,

whereas Cali et al. [19] showed that the relationship between the gestational sac of

the cesarean scar pregnancy, the previous cesarean scar, and the anterior uterine

wall thickness could be used to predict not only the evolution of the cesarean scar

pregnancy towards the most severe types of AIP, but also clinical outcomes among

these women.

This article is protected by copyright. All rights reserved.

 Prenatal diagnosis of cesarean scar pregnancy is another relevant issue. Cesarean

scar pregnancy can be easily misdiagnosed as a normal intra-uterine pregnancy,

Accepted Article
especially in asymptomatic patients and in those presenting in the late first trimester

of pregnancy, such at the time of the nuchal scan. The location of the center of the

gestational sac relative to the midpoint axis of the uterus at 5–10 weeks of

pregnancy could help in differentiating between cesarean scar pregnancy and intra-

uterine pregnancy. Timor-Tritsch et al. [9] reported that women with a normal intra-

uterine pregnancy have a larger distance from the gestational sac to the midpoint the

axis of the uterus, and that assessing this demonstrated good overall diagnostic

accuracy in identifying cesarean scar pregnancy with sensitivity and specificity of

93% and 99%, respectively. Pregnancy duration at imaging is another important

issue; whereas the gestational sac can assume the shape of the niche in which it

implants in the early first trimester, making the diagnosis of cesarean scar pregnancy

feasible, the sac slowly “moves” towards the uterine cavity and gradually changes

shape with progressing pregnancy, assuming an intracavitary position that could

lead to its misdiagnosis as an intrauterine pregnancy. Despite this, it is suggested,

based on the present findings, that women with a low implantation within or in close

proximity to a previous cesarean scar should be referred to centers with high

expertize for the diagnosis and management of AIP.

In the present study, classical ultrasonography signs of AIP were detected in a large

majority of patients at 11–14 weeks of pregnancy, although this prevalence

increased with advancing pregnancy. This poses the question of whether signs of

This article is protected by copyright. All rights reserved.

 AIP should be looked for at the time of the nuchal scan, at least in patients with low

implantation of the placenta within or in close proximity to the previous cesarean

Accepted Article
scar.

The optimal pregnancy length for imaging in women at risk of AIP has still to be

determined. Prenatal diagnosis of AIP is usually accomplished during the third

trimester of pregnancy but, to the best of our knowledge, no studies have compared

the diagnostic accuracy of ultrasonography in detecting AIP at different points during

pregnancy.

The data from the present study demonstrated that there was no difference in the

prevalence of ultrasonography signs of AIP between the second and third trimester

of pregnancy. In this scenario, it is suggested that every patient with a previous

cesarean delivery and a low-lying placenta or placenta previa detected at the time of

imaging should be referred to centers with high expertise in the diagnosis and

treatment of AIP to rule out this anomaly. However, based on the experience of the

authors of the present study, AIP is a progressive condition and serial follow-up

scans during the third trimester of pregnancy are needed to ascertain the depth and

the topography of invasion, which could only become apparent with advancing

pregnancy.

The severity of placental invasion is one of the major determinants of maternal and

peri-surgical outcomes in women with AIP, and placenta percreta is associated with

a higher burden of morbidity compared with placenta accreta or placenta increta [8].

In the present study, ultrasonography signs of AIP were more likely to be visible in

This article is protected by copyright. All rights reserved.

 women with placenta percreta compared with those who had placenta accrete or

increta, particularly later in pregnancy; this highlights the need for predictive models
Accepted Article
aiming to, not only identify the presence of AIP, but also determine the severity of

placental invasion.

Irrespective of depth, the topography of placental invasion is another strong

determinant of maternal outcome in AIP, with patients who exhibit parametrial

invasion at greater risk of intra- and post-surgical adverse events [8]. Prenatal MRI is

the technique of choice when determining the topography of placental invasion. This

evaluation is usually accomplished by obtaining sagittal images and dividing the

anterior placental invasion into two sectors, delimited by a plane perpendicular to the

upper bladder axis and the uterine sector bordering. The upper posterior bladder wall

is called S1, and the uterine sector adjacent to the lower posterior wall, S2. The

importance of this classification system relies on the fact that it can be used to tailor

the optimal surgical approach. Assessing the topography of placental invasion has

only recently been reported in the literature [18, 19]. In the present study, signs of

vascular invasion of the parametria, identified using color Doppler ultrasonography

were reported in no images obtained at 6–9 weeks of pregnancy, in 18.1% of those

obtained at 11–14 weeks, and 47.6% of those taken during both the second and

third trimesters; further, the visualization of vascular invasion of the parametria was

more common in patients with placenta percreta compared with placenta

accreta/increate among images taken during the second and third trimesters. This

highlights the need for early assessment of the aberrant vascular invasion in patients

affected by AIP during early pregnancy to tailor the optimal surgical approach.

However, further studies are needed to confirm the reliability of ultrasonography in

This article is protected by copyright. All rights reserved.

 comparison to MRI in detecting the topography of placental invasion. Until then, it is

suggested that MRI examinations are performed, especially for patients thought to
Accepted Article
be affected by severe types of placental invasion, to reliably delineate the type and

amount of vascular invasion.

The relatively small sample size of the present study, its retrospective design, and a

lack of stratification of the data by the topography of placental invasion were major

limitations of the present study. Further, to preserve the power of the analysis, it was

not possible to report the distribution of each ultrasonography sign among patients

with placenta accrete and increta separately in view of the relatively small number of

patients. The major strengths included the longitudinal assessment of

ultrasonography signs of AIP starting at the early first trimester of pregnancy and that

data were stratified by the depth of placental invasion.

Future large prospective studies are needed to confirm these findings and to

ascertain whether beginning the longitudinal assessment of women at risk in the

early first trimester of pregnancy could improve the diagnostic accuracy of

ultrasonography in detecting AIP and improving outcomes.

Author contributions

GC, IET-T, JP-J, AM, FFor, GM, FFot, DB, GS, ML, and FDA contributed the design

of the study, data collection, data analysis, and manuscript writing. AF contributed to

data analysis and manuscript writing.

This article is protected by copyright. All rights reserved.

 Conflicts of interest

The authors have no conflicts of interest.

Accepted Article
References

[1] Oyelese Y, Smulian JC. Placenta previa, placenta accreta, and vasa previa.

Obstet Gynecol. 2006; 107: 927-941.

[2] Miller DA, Chollet JA, Goodwin TM. Clinical risk factors for placenta previa-

placenta accreta. Am J Obstet Gynecol. 1997; 177:210-214.

[3] E Jauniaux, D Jurkovic Placenta accreta: pathogenesis of a 20th century

iatrogenic uterine disease. Placenta. 2012; 33; 244-251

[4] Wu S, Kocherginsky M, Hibbard JU. Abnormal placentation: twenty-year

analysis. Am J Obstet Gynecol. 2005; 192: 1458-1461.

[5] Timor-Tritsch IE, Monteagudo A, Cali G, Palacios-Jaraquemada JM, Maymon

R, Arslan AA, Patil N, Popiolek D, Mittal KR. Cesarean scar pregnancy and early

placenta accreta share common histology. Ultrasound Obstet Gynecol. 2014; 43:

383-395.

[6] Timor-Tritsch IE, Monteagudo A, Cali G, Vintzileos A, Viscarello R, Al-Khan A,

Zamudio S, Mayberry P, Cordoba MM, Dar P. Cesarean scar pregnancy is a

precursor of morbidly adherent placenta. Ultrasound Obstet Gynecol. 2014; 44: 346-

353.

[7] Zosmer N, Fuller J, Shaikh H, Johns J, Ross JA. Natural history of early first-

trimester pregnancies implanted in Cesarean scars. Ultrasound Obstet Gynecol.

2015; 46: 367-375.

[8] D'Antonio F, Palacios-Jaraquemada J, Lim PS, Forlani F, Lanzone A, Timor-

Tritsch I, Cali G. Counseling in fetal medicine: evidence-based answers to clinical

This article is protected by copyright. All rights reserved.

 questions on morbidly adherent placenta. Ultrasound Obstet Gynecol. 2016;47: 290-

301.
Accepted Article
[9] Timor-Tritsch IE, Monteagudo A, Cali G, El Refaey H, Kaelin Agten A, Arslan

AA. Easy sonographic differential diagnosis between intrauterine pregnancy and

cesarean delivery scar pregnancy in the early first trimester. Am J Obstet Gynecol.

2016 Feb 17. pii: S0002-9378(16)00316-1.

[10] Rac MW, Dashe JS, Wells CE, Moschos E, McIntire DD, Twickler DM.

Ultrasound predictors of placental invasion: the Placenta Accreta Index. Am J Obstet

Gynecol 2015;212:343.e1–7.

[11] Timor-Tritsch IE, Monteagudo A, Bennett TA, Foley C, Ramos J, Agten Kaelin

A. A new minimally invasive treatment for cesarean scar pregnancy and cervical

pregnancy. Am J Obstet Gynecol 2016 Mar 12. pii: S0002-9378(16)00472-5.

[12] Timor-Tritsch IE, Cali G, Monteagudo A, Khatib N, Berg RE, Forlani F,

Avizova E. Foley balloon catheter to prevent or manage bleeding during treatment

for cervical and Cesarean scar pregnancy. Ultrasound Obstet Gynecol. 2015; 46:

118-123.

[13] Timor-Tritsch IE, Monteagudo A, Santos R, Tsymbal T, Pineda G, Arslan AA.

The diagnosis, treatment, and follow-up of cesarean scar pregnancy. Am J Obstet

Gynecol. 2012; 207: 44.e1-13.

[14] Collins SL, Ashcroft A, Braun T, Calda P, Langhoff-Roos J, Morel O,

Stefanovic V, Tutschek B, Chantraine F; European Working Group on Abnormally

Invasive Placenta (EW-AIP). Proposal for standardized ultrasound descriptors of

abnormally invasive placenta (AIP). Ultrasound Obstet Gynecol. 2016; 47: 271-275.

[15] D’Antonio F, Timor-Trisch I, Palacios-Jaraquemada J, Monteagudo A, Buca

D, Forlani F, Minneci G, Foti F, Manzoli M, Liberati M, Acharya G. First trimester

This article is protected by copyright. All rights reserved.

 detection of abnormally invasive placenta in women at risk: a systematic review and

meta-analysis Ultrasound Obstet Gynecol, 2017 [epub ahead of print].

Accepted Article
[16] Benirschke K, Kaufmann P, Baergen RN. Pathology of the human placenta.

5th ed. New York: Springer-Verlag; 2006.

[17] von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke

JP; STROBE Initiative. The Strengthening the Reporting of Observational Studies in

Epidemiology (STROBE) statement: guidelines for reporting observational studies. J

Clin Epidemiol. 2008; 61:344-349.

[18] Kaelin Agten A, Cali G, Monteagudo A, Oviedo J, Ramos J, Timor-Tritsch I.

The clinical outcome of cesarean scar pregnancies implanted "on the scar" versus

"in the niche". Am J Obstet Gynecol. 2017; 216:510.e1-510.e6.

[19] Cali G, Forlani F, Minneci G, Foti F, Di Liberto S, Familiari A, Scambia G,

D'Antonio F. First trimester prediction of surgical outcome in abnormal invasive

placenta using the cross-over sign. Ultrasound Obstet Gynecol. 2017 Feb 24. doi:

10.1002/uog.17440.

Figure 1 Ultrasonography assessment of a patient with abnormally invasive placenta

during the first trimester of pregnancy: Abbreviations: Bl, bladder; P, placenta.

Supplementary table S1 Comparison of the distribution of ultrasonography signs

suggestive of abnormally invasive placenta between the early first (6–9 weeks) and

first (11–14 weeks), trimesters of pregnancy.

This article is protected by copyright. All rights reserved.

 Supplementary table S2 Comparison of the distribution of ultrasonography signs

suggestive of abnormally invasive placenta between the first (11–14 weeks) and
Accepted Article
second (15–24 weeks) trimesters of pregnancy.

Supplementary table S3 Comparison of the distribution of ultrasonography signs

suggestive of abnormally invasive placenta between the second (15–24 weeks) and

third (25–36 weeks) trimesters of pregnancy.

Table 1 Participant characteristics. a

Characteristic All patients Placenta accreta/increta Placenta percreta P

(n=105) (n=57) (n=48) value
Maternal age, y 31 (27–35) 31 (27–36) 31 (27–34) >0.99
Duration of pregnancy at delivery, 35 (31–33) 36 (31–32) 34 (31–32) 0.002
wk
Previous cesarean delivery 105 56 49 >0.99
Previous uterine surgery 18 6 12 0.069
Placental location
Anterior 105 56 49 >0.99
Posterior 0 0 0 >0.99
Ultrasonography examination
data available
6–9 wk 68 (64.8) 36 (63.2) 32 (66.7) 0.838
11–14 wk 83 (79.0) 45 (78.9) 38 (79.2) >0.99
15–24 wk 105 (100.0) 57 (100.0) 48 (100.0) >0.99
25–36 wk 105 (100.0) 57 (100.0) 48 (100.0) >0.99

a
Values are given as median (inter-quartile range), number, or number (percentage), unless indicated
otherwise.

This article is protected by copyright. All rights reserved.

ccepted Articl
Table 2 Distribution of ultrasonography indicators of AIP through pregnancy. a

Ultrasonography finding Early first First trimester (11–14 Second trimester (15–24 Third trimester (25–36 wk) P value b
trimester (6–9 wk) wk)
wk)

All AIP 68 83 105 105

Low implantation of the 68 (100, 94.7– 23 (27.7, 18.4–38.6) <0.001 c
gestational sac 100.0)

Middle implantation of 0 (0, 0.0–5.3) 59 (71.1, 60.1–80.6) <0.001 c

the gestational sac

Loss of the clear zone 0 (0, 0.0–5.3) 70 (84.3, 74.7–91.4) 93 (88.6, 80.9–94.0) 97 (92.4, 85.5–96.7) <0.001

Placental lacunae 0 (0, 0.0–5.3) 65 (78.3, 67.9–86.6) 105 (100.0, 96.5–100.0) 105 (100.0, 96.5–100.0) <0.001

Bladder wall interruption 0 (0, 0.0–5.3) 63 (75.9, 65.3–84.6) 92 (87.6, 79.8–93.2) 98 (93.3, 86.7–97.3) <0.001

Uterovesical 0 (0, 0.0–5.3) 43 (51.8, 40.6–62.9) 83 (79.0, 70.0–86.4) 85 (81.0, 72.1–88.0) <0.001
hypervascularity
Vascular invasion of the 0 (0, 0.0–5.3) 15 (18.1, 10.5–28.0) 50 (47.6, 37.8–57.6) 50 (47.6, 37.8–57.6) <0.001
parametria

Placenta accreta/increta 36 45 57 57

Low implantation of the 36 (100.0, 14 (31.1, 18.2–46.6) <0.001 c

gestational sac 90.3–100.0)

This article is protected by copyright. All rights reserved.

ccepted Articl
Middle implantation of
the gestational sac
0 (0, 0.0–9.7) 29 (64.4, 48.8–78.1) <0.001 c

Loss of the clear zone 0 (0, 0.0–9.7) 35 (77.8, 62.9–88.8) 45 (78.9, 66.1–88.6) 49 (86.0, 74.2–93.7) <0.001

Placental lacunae 0 (0, 0.0–9.7) 34 (75.6, 60.5–87.1) 57 (100.0, 93.7–100.0) 57 (100.0, 93.7–100.0) <0.001

Bladder wall interruption 0 (0, 0.0–9.7) 29 (64.4, 48.8–78.1) 44 (77.2, 64.2–87.3) 50 (87.7, 76.3–94.9) <0.001

Uterovesical 0 (0, 0.0–9.7) 20 (44.4, 29.6–60.0) 35 (61.4, 47.6–64.0) 37 (64.9, 51.1–77.1) <0.001
hypervascularity
Vascular invasion of the 0 (0, 0.0–9.7) 8 (17.8, 8.0–32.1) 17 (29.8, 18.4–43.4) 17 (29.8, 18.4–43.4) <0.001
parametria

Placenta percreta 32 38 48 48
Low implantation of the 32 (100.0, 9 (23.7, 11.4–40.2) <0.001 c
gestational sac 89.1–100.0)

Middle implantation of 0 (0, 0.0–10.9) 30 (78.9, 62.7–90.4) <0.001 c

the gestational sac

Loss of the clear zone 0 (0, 0.0–10.9) 35 (92.1, 78.6–98.3) 48 (100.0, 92.6–100.0) 48 (100.0, 92.6–100.0) <0.001

Placental lacunae 0 (0, 0.0–10.9) 31 (81.6, 65.7–92.3) 48 (100.0, 92.6–100.0) 48 (100.0, 92.6–100.0) <0.001

Bladder wall interruption 0 (0, 0.0–10.9) 34 (89.5, 75.2–97.1) 48 (100.0, 92.6–100.0) 48 (100.0, 92.6–100.0) <0.001

This article is protected by copyright. All rights reserved.

ccepted Articl
Uterovesical
hypervascularity
0 (0, 0.0–10.9) 23 (60.5, 43.4–76.0) 48 (100.0, 92.6–100.0) 48 (100.0, 92.6–100.0) <0.001

Vascular invasion of the 0 (0, 0.0–10.9) 7 (18.4, 7.7–34.3) 33 (68.8, 53.7–81.3) 33 (68.8, 53.7–81.3) <0.001
parametria

Abbreviation: AIP, abnormally invasive placenta.

a
Values are given as number or number (percentage, 95% confidence interval), unless indicated otherwise.
b 2
χ test for trends unless indicated otherwise.
c
Fisher exact test.

This article is protected by copyright. All rights reserved.

ccepted Articl
Table 3 Distribution of ultrasonography indicators of abnormally invasive placenta based on the severity of invasion.

Ultrasonograp Early first trimester (6–8 wk) First trimester (11–14 wk) Second trimester (15–24 wk) Third trimester (25–36 wk)
hy finding
Placenta Placenta P Placenta Placenta P Placenta Placenta P Placenta Placenta P
accreta/inc percreta value accreta/increta percreta value accreta/increta percreta value accreta/increti percreta value
retin (n=32) (n=45) (n=38) (n=57) (n=48) n (n=57) (n=48)
(n=36)
Low 36 (100, 32 (100, >0.99 14 (31.1, 9 (23.7, 0.473
implantation 90.3–100) (89.1– (18.2–46.6) (11.4–
of the 100.0) 40.2)
gestational
sac
Middle 0 (0, 0.0– 0 (0, 0.0– >0.99 29 (64.4, 30 (78.9, 0.223
implantation 9.7) 10.9) 48.8–78.1) 62.7–
of the 90.4)
gestational
sac
Loss of the 0 (0, 0.0– 0 (0, 0.0– >0.99 35 (77.8, 35 (92.1, 0.128 45 (78.9, 48 (100.0, 0.000 49 (86.0, 48 (100.0, 0.007
clear zone 9.7) 10.9) 62.9–88.8) 78.6– 66.1–88.6) 92.6– 4 74.2–93.7) 92.6–
98.3) 100.0) 100.0)
Placental 0 (0, 0.0– 0 (0, 0.0– >0.99 34 (75.6, 31 (81.6, 0.598 57 (100.0, 48 (100.0, >0.99 57 (100.0, 48 (100.0, >0.99
lacunae 9.7) 10.9) 60.5–87.1) 65.7– 93.7–100.0) 92.6–100) 9 93.7–100.0) 92.6–
92.3) 100.0)
Bladder wall 0 (0, 0.0– 0 (0, 0.0– >0.99 29 (64.4, 34 (89.5, 0.010 44 (77.2, 48 (100.0, 0.000 50 (87.7, 48 (100.0, 0.015
interruption 9.7) 10.9) 48.8–78.1) 75.2– 64.2–87.3) 92.6–100) 2 76.3–94.9) 92.6–
97.1) 100.0)
Uterovesical 0 (0, 0– 0 (0, 0.0– >0.99 20 (44.4, 23 (60.5, 0.187 35 (61.4, 48 (100.0, <0.00 37 (64.9, 48 (100.0, <0.00
hypervascular 9.7) 10.9) 29.6–60.0) 43.4– 47.6–64.0) 92.6–100) 01 51.1–77.1) 92.6– 1
ity 76.0) 100.0)
Vascular 0 (0, 0– 0 (0, 0.0– >0.99 8 (17.8, 8.0– 7 (18.4, >0.99 17 (29.8, 33 (68.8, <0.00 17 (29.8, 33 (68.8, <0.00
invasion of 9.7) 10.9) 32.1) 7.7–34.3) 18.4–43.4) 53.7– 01 18.4–43.4) 53.7– 1
the 81.3) 81.3)
parametria
a
Values are given as number or number (percentage, 95% confidence interval), unless indicated otherwise.

This article is protected by copyright. All rights reserved.

Accepted Article

This article is protected by copyright. All rights reserved.